The ERBB/EGFR family member HER4/ERBB4 has critical functions during normal development and influences the progression of human cancer. Proteolytic processing of ERBB4 at the cell surface releases an independently signaling ERBB4 intracellular domain (4ICD) with multiple divergent cellular activities. On the one hand 4ICD translocates to the nucleus in response to estrogen and coactivates gene expression by selectively binding with estrogen receptor to a subset of estrogen response gene promoters. On the other hand an ERBB4 ligand, HRG, promotes 4ICD translocation to mitochondria where 4ICD induces tumor cell apoptosis by functioning as a novel BH3-only protein (proapoptotic members of the BCL-2 family). Despite experimental descriptions of novel 4ICD activities, this unique signaling paradigm remains to be substantiated in physiologically relevant biological systems. Nuclear 4ICD within mammary epithelium coincident with the essential contributions of ERBB4 to lactation supports the hypothesis that 4ICD contributes to mammopoesis. We also hypothesize that novel 4ICD signaling events regulate estrogen activity in breast tumor cells and mediate the response of breast cancer patients to endocrine therapy. We propose to test these related hypotheses by pursuing the following specific aims: Using mice with mutant ERBB4 alleles that abolish proteolytic processing we propose to (Aim 1) identify the contribution of ERBB4 processing and 4ICD nuclear localization to mammary gland development. We propose to employ global gene expression and promoter binding assays to (Aim 2) identify the molecular basis of coupled 4ICD/ER? signaling contributing to breast tumor cell proliferation. Clinical studies suggest that women with tumors coexpressing ER? and ERBB4 fare better when treated with endocrine therapy then women lacking tumor ERBB4 expression. Our data demonstrates that the 4ICD BH3-only protein is a key regulator of tamoxifen response and extinguished breast tumor cell expression of 4ICD results in tamoxifen resistance. We propose to (Aim 3) test the hypothesis that tumor expression of ERBB4/4ICD can be used a marker to predict clinical response to tamoxifen. We predict that our results will represent the first physiologically relevant contribution to the emerging field of cell-surface receptor signaling to the nucleus and have a major impact on therapeutic decisions affecting over 70% of breast cancer patients. PUBLIC HEALTH RELEVANCE: Results from the proposed experiments will stimulate an intellectual and experimental paradigm shift with an emphasis on ERBB4/4ICD as a critical regulator of tamoxifen response in breast cancer patients. Thus we predict that our results will impact the majority of breast cancer patients and lay the foundation for the development of ERBB4/4ICD as an important tumor marker predicting clinical response to tamoxifen. By extension ERBB4/4ICD expression will be used to guide therapeutic decisions with patients with ERBB4/ER(+) tumors benefiting from tamoxifen whereas patients with ERBB4(-)/ER(+) tumors would be better served with a clinical regimen where tamoxifen was augmented or supplanted by another therapeutic approach.